Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation
Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation
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DOI：
10.1126/scitranslmed.aaf9087
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发表时间：
2016-09-28
影响因子：
17.1
通讯作者：
Erbay, Ebru
中科院分区：
文献类型：
--
作者：
Cimen, Ismail;Kocaturk, Begum;Erbay, Ebru
从头脂肪生成（DNL），即葡萄糖和其他底物转化为脂质，通常与异位脂质积聚、代谢应激和胰岛素抵抗有关，尤其是在肝脏中。然而，器官特异性DNL也可以产生具有有益的代谢生物活性的独特脂质，这引起了人们对它们用于治疗代谢疾病的极大兴趣。棕榈油酸酯（PAO），一种这样的生物活性脂质，调节肝脏中的脂质代谢，并提高骨骼肌中的葡萄糖利用，当它从肥胖脂肪组织从头产生时。我们发现，PAO治疗引起了整体脂质重构的内质网（ER）膜在巨噬细胞和小鼠组织，这是与高血压应激的ER的抗性。通过防止ER应激，PAO阻断小鼠和人巨噬细胞中脂质诱导的炎性小体活化。慢性PAO补充还降低了高脂血症小鼠体内全身白细胞介素-1 β（IL-1 β）和IL-18的浓度。此外，PAO在体内防止动脉粥样硬化斑块中的巨噬细胞ER应激和IL-1 β产生，导致斑块巨噬细胞的显著减少和对小鼠动脉粥样硬化的保护。这些发现表明，口服补充DNL的产物如PAO可以促进与细胞内细胞器对脂质应激的代谢弹性相关的膜重塑，并限制动脉粥样硬化的进展。这些发现支持治疗性PAO补充剂作为一种潜在的预防方法，用于预防复杂的代谢和炎症性疾病，如动脉粥样硬化，这需要在人类中进行进一步的研究。
De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1 beta (IL-1 beta) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1 beta production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.